The emergence of multi-drug resistant tuberculosis (TB) threatens our ability to control this highly transmissible and deadly disease. The NIH has recognized this threat and research that will result in greater understanding of the natural history of TB has been encouraged by the release of PA-04-119. This application responds to PA-04-119 by investigating a novel aspect of the pulmonary immune response to TB. Specifically, we show for the first time data that demonstrate a role for the cytokine IL-12p40 in the Mycobacterium tuberculosis (Mtb)-induced migration of pulmonary dendritic cells (DC) from the lung to the draining lymph node (LN). We also show that in the absence of this pathogen-induced migration there is little to no induction of an antigen-specific CD4 T cell response and also a complete loss of immune-mediated protection against disease. This novel observation regarding the role of IL-12p40 in the natural history of TB provides a basis for investigation of the mechanisms whereby IL-12p40 mediates its effects on pulmonary DC. By understanding the role of this cytokine in microbially induced DC migration we will impact not only TB but also other class A, B or C pathogens that enter via the lung and are controlled by CD4 T cell-mediated immune responses. The objective of this proposal is to examine the pathway whereby Mtb induces IL-12p40 within the lung and determine the mechanism whereby IL-12p40 mediates the Mtb-induced migration of DC. By elucidating the mechanism of action of IL-12p40 on DC we will gain insight into how Mtb modulates the induction of the immune response. In Aim One we will determine which cells in the lung are required to produce IL-12p40 in response to Mtb in order for DC migration to occur. We will also determine which receptors are required to initiate and propagate the migration of DC. In Aim Two we will determine the extent to which IL-12p40 is capable of modulating the ability of DC to respond to a chemokine gradient. We will determine whether IL-12p40 alone is sufficient to mediate DC migration or whether a microbial signal is essential to this process. If we determine that IL-12p40 is capable of initiating migration of pulmonary DC then in the future we will examine the ability of IL-12p40 stimulated DC to initiate cellular responses within the lung. In the long term this could provide the basis for an IL-12p40 based adjuvant for vaccines delivered via the pulmonary route. The relevance of this work to public health is that it will increase our understanding of the response of the body to bacterial invasion. This increased understanding will allow targeted and novel interventions that will improve our ability to control disease.